Tissue Factor Pathway Inhibitor (TFPI) and Haemorrhagic Manifestations in Haemophilia A and B Patients

Hemophilia Clinical Trial

Official title:

Tissue Factor Pathway Inhibitor (TFPI) and Haemorrhagic Manifestations in Haemophilia A and B Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02540187
• Other study ID #: 1108164
• Status: Completed
• Phase: N/A
• First received: September 1, 2015
• Last updated: March 9, 2016
• Start date: February 2012
• Est. completion date: February 2016

Study information

• Verified date: March 2016
• Source: Centre Hospitalier Universitaire de Saint Etienne
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Observational

Clinical Trial Summary

Haemophilia is a rare and serious congenital defect of blood coagulation due to a genetic mutation on a sexual chromosome. It affects quasi-essentially the men and it is responsible for bleeding. There are two types of haemophilia: Haemophilia A, (85 % of cases), due to a factor VIII (FVIII) deficiency and Haemophilia B (15 % of cases) due to factor IX (FIX) deficiency. According to the intensity of the defect, there are three forms of haemophilia: severe (FVIII or FIX lower than 1 %), moderate (factor level between 1 and 5 %), minor (factor level between 5 and 40 %). For a same level of factor VIII or IX, hemorrhagic manifestations are variable from one patient to the other. Moreover, several studies showed that haemophilic B patients bleed less and consume fewer anti-hemophilic concentrate that haemophilic A patients.

The main inhibitors of the coagulation are antithrombin, Protein C-Protein S-Thrombomodulin system, and tissue factor pathway inhibitor (TFPI). TFPI is the specific and exclusive inhibitor of tissue factor pathway that is the main way by which plasmatic coagulation starts. TFPI is a potent direct inhibitor of factor Xa and Xa-dependent inhibitor of the VIIa-Tissue Factor (TF) complex. In hemophilic patient, the production of Xa by the amplification pathway being strongly altered because of factor VIII or IX deficiency, thrombin generation (via Xa) comes exclusively from TFPI regulated tissue factor pathway. We can thus say that if haemophilic patients bleed, it is also because of the presence of TFPI that inhibits at the same time Xa and the complex TF-VIIa as soon as factor Xa is generated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 164
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Haemophilia A and B patients between 18 and 65 years old, whatever the severity of their disease, who have signed the informed consent form

• On-demand or on prophylactic therapy.

• Regular monitoring in investigator center.

Exclusion Criteria:

• - Haemophilia patients under 18.

• Presence of an inhibitor at any time before or during the study period.

• Patients who received factor VIII concentrate less than 72 hours or factor IX concentrate less than 96 hours before blood collection

• Patients who refused to sign informed consent

• Patient data over the last 5 years at least not available.

• No regular monitoring in haemophilia center (required at least one visit every 18 months for severe or moderate hemophiliac patients).

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Hemophilia
• Hemophilia A

Intervention

Other:
• blood specimen

Locations

Country	Name	City	State
France	CHRU Lille	Lille
France	HCL	Lyon
France	AP-HM	Marseille
France	Chu Nancy	Nancy
France	Chu Reims	Reims
France	CHU Saint-Etienne	Saint-Etienne
France	Chu Tours	Tours

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Saint Etienne	Pfizer

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Comparison for TFPI level between Haemophilia A and Haemophilia B	Comparison for TFPI level between Haemophilia A and Haemophilia B	day 1	No
Primary	Comparison for TFPI level between severe Haemophilia A and severe Haemophilia B	Comparison for TFPI level between severe Haemophilia A and severe Haemophilia B	Day 1	No
Primary	Comparison for TFPI level between moderate or mild Haemophilia A and moderate or mild Haemophilia B	Comparison for TFPI level between moderate or mild Haemophilia A and moderate or mild Haemophilia B	Day 1	No
Secondary	Correlation between free TFPI and hemorrhagic score	Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score (HSS). It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.; For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.; Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations	day 1	No
Secondary	Correlation between TFPI activity and hemorrhagic score	Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.; For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.; TFPI activity will be measured according to the technique described and modified by Sandset	day 1	No
Secondary	Correlation between Endogenous Thrombin Potential (ETP) and free TFPI	Endogenous Thrombin Potential (i.e. the aera under the thrombin generation curve, nM.min) is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations	day 1	No
Secondary	Correlation between Lag Time and free TFPI	Lag time (min) of the thrombin Generation curve is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations	day 1	No
Secondary	Correlation between Peak value and free TFPI	Peak Value (PV, nmol thrombin) of the thrombin Generation curve is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations	day 1	No
Secondary	Correlation between Time to Peak and free TFPI	Time to Peak (TTP, min) of the thrombin Generation curve is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations	day 1	No
Secondary	Correlation between ETP and hemorrhagic score	Endogenous Thrombin Potential (i.e. the aera under the thrombin generation curve, nM.min) is measured by Thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.; For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.	day 1	No
Secondary	Correlation between Lag Time and hemorrhagic score	Lag time (min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.; For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.	day 1	No
Secondary	Correlation between Peak Value and hemorrhagic score	Peak Value (PV, nmol thrombin) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.; For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.	day 1	No
Secondary	Correlation between Time to Peak and hemorrhagic score	Time to Peak (TTP, min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.; For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.	day 1	No
Secondary	Comparison for ETP between haemophilia A et Haemophilia B	Endogenous Thrombin Potential (i.e. the aera under the thrombin generation curve, nM.min) is measured by Thromboplastin Generation Test (TGTs)	Day 1	No
Secondary	Comparison for lag time between haemophilia A et Haemophilia B	Lag time (min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs)	Day 1	No
Secondary	Comparison for Peak Value between haemophilia A et Haemophilia B	Peak Value (PV, nmol thrombin) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs)	Day 1	No
Secondary	Comparison for Time to Peak between haemophilia A et Haemophilia B	Time to Peak (TTP, min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs)	day 1	No